Hypothyroidism is a common medical problem easily treated when diagnosed but requiring regular follow-up and patient medication compliance. At times, this diagnosis can go untreated resulting in the development of severe consequences such as Myxedema Coma. Of all the clinical symptoms, cardiovascular manifestations tend to be especially severe and often life threatening.

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Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Upregulation of inhibitory signaling pathways (such as T cell Ig and mucin domain protein-3 [Tim-3]) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. Although the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3+ Tregs is poorly explored. In this study, we investigated whether and how the Tim-3 pathway alters Foxp3+ Treg development and function in patients with chronic HCV infection. We found that Tim-3 was upregulated, not only on IL-2-producing CD4+CD25 +Foxp3- Teffs, but also on CD4+CD25 +Foxp3+ Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared with healthy subjects. Tim-3 expression on Foxp3+ Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but it was inversely associated with proliferation of IL-2-producing Teffs. Moreover, Foxp3+ Tregs were found to be more resistant to, and Foxp3- Teffs more sensitive to, TCR activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4+CD25+ T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3+ Tregs/Foxp3- Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control Treg and Teff balance through altering cell proliferation and apoptosis during HCV infection.

Nuclear receptors (NRs) play crucial roles in the regulation of hepatic cholesterol synthesis, metabolism, and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured murine cholangiocytes and found that these cells express a specific subset of NRs, including liver X receptor (LXR) β and peroxisome proliferator-activated receptor (PPAR) δ. Activation of LXRβ and/or PPARδ in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARδ induces Niemann-Pick C1-like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane via specific interaction with a peroxisome proliferator-activated response element (PPRE) within the NPC1L1 promoter. Conclusion: We propose that (1) LXRβ and PPARδ coordinate NPC1L1/ABCA1-dependent vectorial cholesterol flux from bile through cholangiocytes and (2) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, two serious health concerns for humans.

We review the emerging concept that changes in cellular bioenergetics concomitantly reprogram inflammatory and metabolic responses. The molecular pathways of this integrative process modify innate and adaptive immune reactions associated with inflammation, as well as influencing the physiology of adjacent tissue and organs. The initiating proinflammatory phase of inflammation is anabolic and requires glucose as the primary fuel, whereas the opposing adaptation phase is catabolic and requires fatty acid oxidation. The fuel switch to fatty acid oxidation depends on the sensing of AMP and NAD+ by AMPK and the SirT family of deacetylases (e.g., SirT1, -6, and -3), respectively, which couple inflammation and metabolism by chromatin and protein reprogramming. The AMP-AMPK/NAD+-SirT axis proceeds sequentially during acute systemic inflammation associated with sepsis but ceases during chronic inflammation associated with diabetes, obesity, and atherosclerosis. Rebalancing bioenergetics resolves inflammation. Manipulating cellular bioenergetics is identifying new ways to treat inflammatory and immune diseases.

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